Functional characterization of the 9q34.13 locus identifies RAPGEF1 as a candidate gene modulating risk for melanoma and nevi via RAS activation.

Higher RAPGEF1 levels are linked to increased melanoma and nevus risk by promoting RAS activation in melanocytes.

• Why it matters: Understanding genetic factors that influence melanoma and nevus development can improve risk prediction and targeted therapies, especially for tumors lacking RAS-MAPK pathway mutations.
• What they did: The study used fine-mapping, expression data, colocalization analyses, and CRISPR inhibition to identify regulatory variants affecting RAPGEF1, demonstrating its role in melanocyte growth and RAS pathway activation.
• The result: Elevated RAPGEF1 expression correlates with melanoma tumors lacking RAS or BRAF mutations, suggesting it may promote oncogenic RAS signaling and serve as a prognostic marker in specific melanoma subtypes.